2- Or 3- aryl substituted imidazo [1,2-a]pyridines

ABSTRACT

Novel 2- or 3- aryl substituted imidazo[1,2-a]pyridines and their synthesis are described. The compounds have local anesthetic properties and are useful as local anesthetic agents.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel 2- or 3- aryl substitutedimidazo[1,2-a]pyridines of general formula: ##STR1## as describedfurther below. The compounds of formula I are useful as local anestheticagents.

2. Description of the Prior Art

No examples of local anesthetics with a 2- or 3- aryl substitutedimidazo[1,2-a]pyridine structure have been seen in the prior art.

Local anesthetics are drugs which reversibly block nerve conduction neartheir site of application or injection and thus produce temporary lossof feeling or sensation in a limited area of the body. Local anestheticsare used to prevent pain in surgical procedures, injury, and disease.Local anesthetics can act on any part of the nervous system and on everytype of nerve fiber. Since ionic mechanisms of excitability are similarin nerve and muscle, it is not surprising that local anesthetics alsohave prominent actions on all types of muscular tissue.

Local anesthetics prevent both the generation and the conduction of anerve impulse. The main site of action is the cell membrane, and thereis seemingly little direct action of physiological importance on theaxoplasm. The axoplasmic effects that do occur may be secondary to themembrane action.

Known local anesthetics block conduction by interfering with thefundamental process in the generation of a nerve action potential,namely, the large transient increase in the permeability of the membraneto sodium ions that is produced by a slight deplarization of themembrane.

One theory of how local anesthetics block nerve conduction is that theycompete with calcium at some site that controls the permeability of themembrane. Local anesthetics also reduce the permeability of restingnerve to potassium as well as to sodium ions.

Adverse reactions to local anesthetics can be divided into two groups:systemic and local adverse reactions. Systemic adverse reactions areusually associated with high blood levels of the drug and usually resultfrom overdosage, rapid systemic absorption, or inadvertant intravenousadministration. The reactions usually involve the central nervous andcardiovascular systems. Local adverse reactions to known localanesthetic drugs are either cytotoxic or allergic.

SUMMARY OF THE INVENTION

The present invention is directed to 2- or 3- aryl substitutedimidazo[1,2-a]pyridines of the formula ##STR2## where X may be hydrogen,one or more of halogen, hydroxy, alkoxy having 1-3 carbon atoms,benzyloxy, or C₁ -C₆ alkyl.

R may be H or Ar,

R₁ may be H, CH₃ or Ar;

Ar may be ##STR3## R₂ may be a C₁ -C₆ alkyl; n may be 0 or 1 when R isAr; or

n may be 1 when R₁ is Ar is bonded at C-3; and

m may be 2-6, with the provision that both R and R₁ cannot be Ar at thesame time.

The compounds of formula 1 are useful as local anesthetic compounds.

DETAILED DESCRIPTION OF THE INVENTION

The invention in its broadest aspects relates to 2- or 3- arylsubstituted imidazo[1,2-a]pyridine compounds which have local anestheticactivity in mammals. The 2- or 3- aryl substitutedimidazo[1,2-a]pyridine compounds of the invention demonstrating localanesthetic activity are shown above.

The preferred compounds of the present invention are those wherein X ishydrogen, bromo, hydroxy, benzyloxy, methyl or dimethyl; R₂ is butyl;and m is 3.

The 2-aryl substituted imidazo[1,2-a]pyridine compounds where n is 0 areprepared in accordance with Scheme 1. ##STR4##

In Scheme I, p-hydroxyacetophenone or p-hydroxypropiophenone, R₁ is H orCH₃ respectively, is treated with a 1-bromo-ω-chloro alkane such as1-bromo-2-chlorethane, 1-bromo-3-chloropropane, 1-bromo-4-chlorobutaneor 1-bromo-5-chloropentane or 1-bromo-6-chlorohexane by refluxing in analcoholic base for about 12 to 48 hours to produce ap-chloroalkoxyphenone 1 as a liquid. The alcohol is preferably methanol,and the base may be potassium hydroxide or sodium hydroxide.

The p-chloroalkoxyphenone 1 is then reacted with bromine in either anether solvent or glacial acetic acid or carbon disulfide. Suitableethers include tetrahydrofuran, diethyl ether, or dimethoxy ether. Thereaction takes place at a temperature of about 10° C. to 65° C. forabout 2 to 24 hours to produce α-bromo-ketone 2.

The α-bromoketone 2 is then subjected to a condensation reaction with2-aminopyridine or a substituted 2-aminopyridine in an alcoholicsolvent. The condensation is conducted at about 65° C. to 86° C. forabout 2 to 24 hours to yield the chloroalkoxyphenyl imidazopyridine 3.Suitable substituted 2-aminopyridines which may be utilized in thecondensation reaction include 3-methyl-2-aminopyridine,5-bromo-2-aminopyridine, 4-methyl-2-aminopyridine,3-benzyloxy-2-aminopyridine, 3-hydroxy-2-aminopyridine, and4,6-dimethyl-2-aminopyridine. The alcoholic solvent may be methanol,ethanol or isopropanol.

The chloroalkoxyphenyl imidazopyridine 3 is treated with an aminesolvent, such as dimethylamine, diethylamine, dipropylamine,dibutylamine, dipentylamine or dihexylamine at about 100° C. to 150° C.for 4 to 64 hours to yield the 2-aryl substitutedimidazo-[1,2-a]pyridine 4.

The 2-aryl substituted imidazo pyridines where n is 1 are producedaccording to Scheme II. ##STR5##

The α-bromoketone 4 which may be prepared as described in Scheme I, istreated in a polar solvent with an aqueous solution of a base, such assodium hydroxide, at about 20° C. to 50° C. to produce α-hydroxyketone5. Suitable polar solvents include dimethylformamide, dimethylsulfoxide, hexamethyl phosphoramide and N-methyl pyrrodlidone.

The α-hydroxyketone 5 is then oxidized with an oxidizing agent, such aspyridinium chlorochromate, chromium trioxidepyridine, dimethylsulfoxide-oxalyl chloride or chromic acidsulfuric acid, in an inertsolvent to yield the diketone 6. Suitable inert solvents includemethylene chloride, chloroform and acetone.

The diketone 6 is reacted with bromine in either an ether solvent orglacial acetic acid or carbon disulfide at about 10° C. to 65° C. forabout 2 to 24 hours to produce the α-bromodiketone 7. Suitable ethersinclude tetrahydrofuran, diethyl ether or dimethoxyether.

The α-bromodiketone 7 is subjected to the condensation as previouslydescribed in Scheme 1 to produce compound 8 which is reacted with anamine solvent as described in Scheme I to yield the 2-aryl substitutedimidazo[1,2-1]pyridines 9.

The 3-aryl substituted imidazo[1,2-a]pyridines where n is 1 are producedin accordance with Scheme III which follows. ##STR6##

In Scheme III, 2-aminopyridine or a substituted 2-aminopyridine, such as3-methyl-2-aminopyridine, 5-bromo-2-aminopyridine,4-methyl-2-aminopyridine or 3-hydroxy-2-aminopyridine reacted withdimethylformamide dimethylacetal or triethyl orthoformate in an inertsolvent at about 60° C. to 120° C. for about 4 to 12 hours to produce anamidine 10. Suitable inert solvents include benzene, toluene, xylenes oracetone.

The amidine 10 is then subjected to a condensation reaction with aα-bromoketone 11 in an alcoholic solvent, such as methanol, ethanol orisopropanol at about 60° C. to 85° C. for about 2 to 24 hours to yield a3-aryl substituted imidazopyridine 12 which is a solid. Theα-bromoketone 11 can be produced by reacting p-hydroxy- acetophenonewith bromine in either an ether solvent or glacial acetic acid or carbondisulfide at a temperature range of about 10° C. to 65° C. forapproximately 2 to 24 hours. Suitable ethers include tetrahydrofuran,diethyl ether or dimethoxy ether.

The 3-aryl substituted imidazopyridine 12 is alkylated with achloroalkyl dialkylamine to yield the 3-aryl substitutedimidazo-[1,2-a]pyridine 13. The reaction is conducted in an alcoholicbase such as potassium hydroxide in methanol and in the presence ofcatalytic iodine at a temperature of about 60° C. to 80° C. for about 8to 9 hours. The chloroalkoxy dialkylamine used in the reaction isprepared by treating a 1-bromo-ω-chloroalkane with a dialkylamine atabout 100° C. to 150° C.

For topical administration, the carrier may take a wide variety of formsdepending on the form of preparation, such as creams, dressings, gels,lotions, ointments or liquids. The 2- or 3- aryl substitutedimidazo[1,2-a]pyridine will be present in the pharmaceutical compositionfrom about 1% by weight to about 10% by weight, depending on theparticular form employed.

An injectable form of the 2- or 3- aryl substitutedimidazo-[1,2-a]pyridine is usually administered intradermally,subcutaneously, or submucosally across the path of nerves supplying thearea to be anethesized. The injection may also be given intramuscularly.The 2- or 3- aryl substituted imidazo-[1,2-a]pyridines will be presentin injectable pharmaceutical composition from about 0.1% by weight to10% by weight. The injectable preparation may also contain isotonicityadjusting agents such as sodium chloride, pH adjusting agents such ashydrochloric acid and preservatives such as methylparaben. Injectablepreparations may be in the form of solutions or suspensions.

Pharmaceutical compositions containing a compound of the presentinvention as the active ingredient in intimate admixture with apharmaceutical carrier can be prepared according to conventionalpharmaceutical compounding techniques.

The following examples describe the invention in greater particularityand are intended to be a way of illustrating but not limiting theinvention.

EXAMPLE 1 2-(4-Dibutylaminopropoxyphenyl)imidazo[1,2-a]pyridine

To a mixture of p-hydroxyacetophenone (50.7 g, 0.37 mol) and1-bromo-3-chloropropane (160 ml, 1.5 mol) in methanol (250 ml) was addedportionwise potassium hydroxide (63 g, 1.12 mol). The mixture wasstirred at reflux for 24 hours, cooled to room temperature, filteredthrough Celite and evaporated in vacuo. The residual semi-solid wasdiluted with diethyl ether (500 ml) and washed with H₂ O (2×300 ml). Theether solution was dried over MgSO₄, filtered and evaporated in vacuo togive p-chloropropoxy acetophenone as a liquid in 68% yield (53.38 g). ¹H NMR (CDCl₃): δ7.98-7.89 (d, J=8.9 Hz, 2H), 7.02-6.92 (d, J=8.9 Hz,2H), 4.16 (t, J=5.9 Hz, 2H), 3.75 (t, J=6.4 Hz, 2H), 2.52 (s, 3H),2.34-2.16 (m, 2H).

To a stirred solution of p-chloropropoxyacetophenone (53.3 g, 0.25 mol)in diethyl ether (250 ml) was slowly added bromine (13 ml, 0.25 mol) andallowed to stir at room temperature for 16 hours. The dark mixture waspoured into an aqueous saturated sodium bicarbonate solution (300 ml)and the organic layer separated. The ether layer was washed with anaqueous saturated sodium bicarbonate solution (300 ml) and with water(300 ml) and dried over MgSO₄. The solution was filtered and evaporatedin vacuo to yield α-bromo-4-chloropropoxy acetophenone (64.4 g, 88%yield) as a dark oil. ¹ H NMR (CDCl₃): δ7.96 (d, J=8.9 Hz, 2H), 6.95 (d,J=8.9 Hz, 2H), 4.41 (s, 2H), 4.19 (t, 2H), 3.75 (t, 2H), 2.26 (m, 2H).

A mixture of α-bromo-4-chloropropoxy acetophenone (12.8 g, 44 mmol) and2-aminopyridine (4.0 g, 44 mmol) in ethanol (80 ml) was stirred atreflux for 3 hours, cooled at room temperature and filtered to give2-(4-chloropropoxyphenyl)imidazo[1,2-a]pyridine (5.2 g, 32% yield) as awhite solid. ¹ H NMR (CD₃ OD): δ8.81 (d, J=6.7 Hz, 1H), 8.51 (s, 1H),7.97-7.01 (m, 7H) 4.19 (t, J=5.9 Hz, 2H), 3.79 (t, J=6.3 Hz, 2H), 2.25(m, 2H).

A suspension of 2-(4-chloropropoxyphenyl)imidazo[1,2-a]-pyridine (5.2 g,14 mmol) in dibutylamine (30 ml) was stirred at reflux for 5 hours. Theexcess dibutylamine was removed by distillation and the resulting oilwas flash chromatographed (silica gel, 9:1 CH₂ Cl₂ : acetone) to givethe free base of the title compound (5.1 g, 93% yield) as an oil. TheHCl salt was prepared by dropwise addition of concentrated hydrochloricacid to a solution of the free base in methanol, concentrated andrecrystallized from methanol acetone to yield2-(4-dibutylaminopropoxyphenyl)imidazo- [1,2-a]pyridine as a whitecrystalline solid, mp 179° C. to 183° C. IR(KBr): 3400, 2620, 1650, 1620cm⁻¹. MS: 380 (MH⁺). ¹ H NMR (CD₃ OD): δ8.80 (d, J=8 Hz, 1H), 8.52 (s,1H), 7.92-7.49 (m, 5H), 7.18 (d, J=8 Hz, 2H), 4.23 (t, J=4.6 Hz, 2H),3.50-3.13 (m, 6H), 2.25 (m, 2H), 1.82-1.34 (m, 8H), 1.01 (m, 6H).

Theor. C₂₄ H₃₃ N₃ O.3HCl: C, 58.95; H, 7.42; N, 8.59. Found: C, 59.25;H, 7.71; N, 9.03.

When in the above procedure, p-hydroxypropiophenone is employed as thestarting material, 2-(4-dibutylaminopropoxy-phenyl)-3-methylimidazo[1,2-a]pyridine is obtained as the resultant product.

EXAMPLE 2 2-(4-Dibutylaminopropoxyphenyl)-8-methylimidazo[1,2-a]pyridine

The title compound was prepared as described above by reacting3-methyl-2-aminopyridine (6.3 g, 15.8 mmol) withα-bromo-4-chloropropoxyacetophenone. The product was reacted withdibutylamine as described above to produce (2.0 g, 32% yield) of thefree base which was converted to the HCl salt, mp 214° C. to 217° C.IR(KBr): 3420, 2960, 1650, 1615 cm⁻¹. MS: 393 (M⁺). ¹ H NMR (CD₃ OD):δ8.25 (d, J=6 Hz, 1H), 8.06 (s, 1H), 7.88 (d, J=7 Hz, 2H), 7.05 (m, 3H),6.85 (t, J=6 Hz, 1H), 4.13 (t, J=4 Hz, 2H), 3.00-2.80 (m, 6H), 2.59 (s,3H), 2.10 (m, 2H), 1.57-1.44 (m, 8H), 1.04 (m, 6H).

Theor. C₂₅ H₃₅ N₃ O.3HCl: C, 59.70; H, 7.62; N, 8.35. Found: C, 59.61;H, 7.69; N, 8.37.

EXAMPLE 3 2-(4-Dibutylaminopropoxyphenyl)-6-bromoimidazo[1,2-a]pyridine

5-Bromo-2-aminopyridine (2.0 g, 12 mmol) was reacted withα-bromo-4-chloropropoxyacetophenone as described in Example 1. Theresulting product was reacted with dibutylamine as described in Example1 to give the free base of the title compound (2.1 g, 74% yield) whichwas converted to the HCl salt, mp 193° C. to 195° C. IR(KBr): 3420,2700, 1650, 1605 cm⁻¹. MS: 358 (M⁺). ¹ H NMR (CD₃ OD): δ9.10 (brs, 1H),8.49 (s, 1H), 8.13-8.01 (dd, J=1.6, 9.6 Hz, 1H), 7.85 (d, J=9.2 Hz, 3H),7.13 (d, J=8.8 Hz, 2H), 4.22 (t, J=6 Hz, 2H), 3.24 (m, 6H), 2.29 (m,2H), 1.66-1.40 (m, 8H). 1.02 (m, 6H).

Theor. C₂₄ H₃₂ BrN₃ O.2HCl.H₂ O: C, 52.47; H, 6.61; N, 7.65. Found: C,52.06; H, 6.47; N, 7.50.

When in the above procedure, p-hydroxypropiophenone is employed as thestarting material,2-(4-dibutylaminopropoxyphenyl)-3-methyl-6-bromoimidazo[1,2-a]pyridineis obtained as the resultant product.

EXAMPLE 4 2-(4-Dibutylaminopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine

The title compound was produced in accordance with Example 1 by reacting4-methyl-2-aminopyridine (1.1 g, 10.3 mmol) withα-bromo-4-chloropropoxyacetophenone and reacting the resulting compoundwith dibutylamine to yield 1.6 g of the compound (29% yield) the HClsalt, mp 134° C. to 136° C. IR(KBr): 3440, 2640, 2510 cm⁻¹. MS: 393(M⁺). ¹ H NMR (CD₃ OD): δ8.63 (d, J=6.7 Hz, 1H), 8.37 (s, 1H), 7.84 (d,J=8.8 Hz, 2H), 7.66 (s, 1H), 7.33 (d, J=6.9 Hz, 1H), 7.17 (d, J=8.8 Hz,2H), 4.22 (t, J=5 Hz, 2H), 3.39-3.13 (m, 6H), 2.60 (s, 3H), 2.28 (m,2H), 1.76-1.40 (m, 8H), 1.02 (m, 6H).

Theor. C₂₅ H₃₅ N₃ O.3HCl.2H₂ O: C, 55.71; H, 7.86; N, 7.80. Found: C,55.57; H, 7.60; N, 7.43.

When is the above procedure, p-hydroxypropiophenone is employed as thestarting material, 2-(4-dibutylaminopropoxyphenyl)3,7-dimethylimidazo[1,2-a]pyridine is obtained as the resultant product.

EXAMPLE 52-(4-Dibutylaminopropoxyphenyl)-8-hydroxyimidazo[1,2-a]pyridine

3-Hydroxy-2-aminopyridine (3.8 g, 34.4 mmol) was reacted withα-bromo-4-chloropropoxyacetophenone as described in Example 1. Theresulting product was reacted with dibutylamine as described in Example1 to produce 5.7 (69% yield) of the free base of the title compound,which was then converted to the HCl salt, mp 174° C. to 177° C. IR(KBr):3450, 1640, 1610 cm⁻¹. MS: 396 (MH⁺). ¹ H NMR (CD₃ OD): δ8.42 (s, 1H),8.29 (d, J=6 Hz, 1H), 7.87 (d, J=9 Hz, 2H), 7.20 (m, 4H), 4.23 (t, J=6Hz, 2H), 3.50-3.15 (m, 6H), 2.29 (m, 2H), 1.84-1.29 (m, 8H), 1.02 (m,6H).

Theor. C₂₄ H₃₃ N₃ O₂.3HCl.1/2H₂ O: C, 56.09; H, 7.26; N, 8.18. Found: C,56.00; H, 7.09; N, 7.99.

When in the above procedure, p-hydroxypropiophenone is employed as thestarting material,2-(4-dibutylaminopropoxy-phenyl)-3-methyl-8-hydroxyimidazo[1,2-a]pyridineis obtained as the resultant product.

EXAMPLE 6 2-(4-Dibutylaminopropoxyphenyl)-8benzyloxyimidazo[1,2-a]pyridine

The title compound, was prepared in accordance with Example 1 byreacting 3-benzyloxy-2-aminopyridine (5.0 g, 25 mmol) withα-bromo-4-chloropropoxyacetophenone and reacting the resulting productwith dibutylamine to yield 6.7 of the free base (73% yield) which wasconverted to the HCl salt, mp 153° C. to 156° C. IR(KBr): 3440, 3960,1620, cm⁻¹. MS: 485 (M⁺). ¹ H NMR (CD₃ OD): δ8.46 (s, 1H), 7.87 (d,J=8.8 Hz, 2H), 7.62-7.37 (m, 2H), 7.16 (d, J=8.8 Hz, 2H), 5.49 (s, 2H),4.22 (t, J=5.8 Hz, 2H) 3.49-3.13 (m, 6H), 2.26 (m, 2H), 1.85-1.27 (m,8H), 1.02 (m, 6H).

Theor. C₃₁ H₃₉ N₃ O₂.2HCl.3/2H₂ O: C, 63.58; H, 7.57; N, 7.18. Found: C,63.69; H, 7.52; N, 7.17.

When in the above procedure, p-hydroxypropiophenone is employed as thestarting material,2-(4-dibutylaminopropoxy-phenyl)-3-methyl-8-benzyloxyimidazo[1,2-a]pyridineis obtained as the resultant product.

When in the procedure of Example 6, 4,6-dimethyl-2-aminopyridinepyridine is used in place of 3-benzyloxy-2-aminopyridine,2-(4-dibutylaminopropoxyphenyl)-5,7-dimethylimidazo[1,2-a]pyridine isobtained as the resultant product.

EXAMPLE 72-(4-Dibutylaminopropoxyphenyl)-3,8-dimethylimidazo[1,2-a]pyridine

p-Hydroxypropiophenone (50 g, 0.33 mmol) was reacted with1-bromo-3-chloropropane and the resulting compound reacted with bromineas described in Example 1. The resulting compound was reacted with3-methyl-2-aminopyridine (1.7 g, 16 mmol) and the product reacted withdibutylamine as described in Example 1 to produce 2.4 g. (62% yield) ofthe title compound as the HCl salt, mp 202° C. to 204° C. IR(KBr): 3420,2620, 1650 1605cm⁻¹. MS: 408 (M⁺). ¹ H NMR (CD₃ OD): δ8.58 (d, J=6.5 Hz,1H), 7.85-7.71 (m, 3H), 7.48 (t, J=6.7 Hz, 1H), 7.22 (d, J=8.7 Hz, 2H),4.26 (t, J=5.8 Hz, 2H), 3.52-3.16 (m, 6H), 2.75 (s, 3H), 2.73 (s, 3H),2.33 (m, 2H), 1.87-1.36 (m, 8H), 1.02 (m, 6H).

Theor. C₂₆ H₃₇ N₃ O.3HCl.H₂ O: C, 58.37; H, 7.91; N, 7.85. Found: C,58.20; H, 7.98; N, 7.67.

When in the above procedure, 4,6-dimethyl-2-aminopyridine is used inplace of 3-methyl-2-aminopyridine,2-(4-dibutylaminopro-poxyphenyl)-3,5,7-trimethylimidazo[1,2-a]pyridineis obtained as the resultant product.

When in any of the above procedures, 1-bromo-2-chlorothane,1-bromo-4-chlorobutane, or 1-bromo-5-chloropentane is used in place of1-bromo-3-chloropropane, the corresponding2-(4-dibutylaminoethoxyphenyl)-substituted imidazo[1,2-a]pyridines,2-(4-dibutylaminobutoxyphenyl)-substituted imidazo[1,2-a]pyridines or2-(4-dibutylaminopentoxyphenyl)-substituted imidazo[1,2-a]-pyridines areobtained.

When in any of the above procedures, dimethylamine, diethylamine,dipropylamine, dipentylamine or dihexylamine is used in place ofdibutylamine, the corresponding 2-(4-dimethyl-, 2-(4-diethyl-,2-(4-dipropyl- 2-4(dipentyl- or2-(4-dihexylaminopropoxyphenyl)-substituted imidazo[1,2-a]pyridinesderivatives are obtained.

EXAMPLE 82-(4-Dibutylaminopropoxybenzoyl)-8-methylimidazo[1,2-a]pyridine

To a solution of a α-bromoketone (60 g, 0.20 mol) in dimethylformamide(120 ml) was slowly added an aqueous solution of sodium hydroxide (8.6g, 0.20 mol, in 50 ml of H₂ O). The mixture was stirred at roomtemperature for 30 minutes, diluted with diethyl ether (500 ml) andwashed once with H₂ O (500 ml). The ether layer was dried over MgSO₄,filtered and concentrated to giveα-hydroxy-(4-chloropropoxy)propiophenone (30.5 g, 65% yield) as a yellowoil. ¹ H NMR (CDCl₃): δ7.93 (d, J=8.9 Hz, 2H), 6.98 (d, J=8.9 Hz, 2H),5.12 (m, 1H), 4.21 (t, J=5.9 Hz, 2H), 3.77 (t, J=6.2 Hz, 2H), 2.28 (m,2H) 1.46 (d, J=6.9 Hz, 3H).

To a solution of α-hydroxy-(4-chloropropoxy)propiophenone (30.5 g, 0.13mol) in methylene chloride (250 ml) was added pyridinium chlorochromate(41 g, 0.19 mol) portionwise. The mixture was stirred at roomtemperature for 24 hours, filtered through Celite and concentrated. Thedark oil was taken up in diethyl ether, (500 ml) filtered again throughCelite then concentrated to give α-keto-(4-chloropropoxy)propiophenone(18.7 g, 62% yield) as an amber oil. ¹ H NMR (CDCl₃): δ8.03 (d, J=8.9Hz, 2H), 6.96 (d, J=8.9 Hz, 2H), 4.21 (t, J=5.9 Hz, 2H), 3.76 (t, J=6.2Hz, 2H), 2.51 (s, 3H) 2.27 (m, 2H).

To a solution of α-keto-(4-chloropropoxy)propiophenone (18.7 g, 77.9mmol) in diethyl ether (300 ml) was added bromine (4 ml, 77.9 mmol)dropwise. The solution was stirred at room temperature for 24 hours thenpoured into an aqueous saturated sodium bicarbonate solution (500 ml).The organic layer was separated, washed once again with an aqueoussodium bicarbonate solution, dried over MgSO₄, filtered and concentratedto give α-bromo-α-keto-(4-chloropropoxy)propiophenone (24.4 g, 98%yield) as an amber oil. ¹ H NMR (CDCl₃): δ8.02 (d, J=8.9 Hz, 2H), 6.99(d, J=8.9 Hz, 2H), 4.40 (s, 2H), 4.23 (t, J=7.5 Hz, 2H), 3.76 (t, J=7.5Hz, 2H) 2.70 (m, 2H).

A solution of 3-methyl-2-aminopyridine (1.6 g, 14.7 mmol) andβ-bromo-α-keto-(4-chloropropoxy)propiophenone (4.7 g, 14.7 mmol) inethanol (50 ml) was stirred at reflux for 3 hours. The mixture wasconcentrated and the resulting semi-solid was recrystallized frommethanol-acetone to give2-(4-chloropropoxybenzoyl)-8-methylimidazo[1,2-a]pyridine as anoff-white solid (2.4 g, 41% yield). ¹ H NMR (CDCl₃): δ9.94 (s, 1H), 9.59(d, J=7.4 Hz, 1H), 8.21 (d, J=8.8 Hz, 2H), 7.73 (m, 1H), 7.10 (d, J=8.8Hz, 2H) 6.74 (t, J=6.9 Hz, 1H), 4.25 (t, J=5.7 Hz, 2H), 3.77 (t, J=6.2Hz, 2H), 2.76 (s, 3H), 2.30 (m, 2H).

A mixture of 2-(4-chloropropoxybenzoyl)-8-methylimidazo-[1,2-a]pyridine(2,4 g, 6.0 mmol) in dibutylamine (30 ml) was stirred at reflux for 8hours. The excess dibutylamine was removed by distillation and theresulting oil was flash chromatographed (silica gel, acetone) to givethe free base of the title compound (2.5 g, 100% yield) as a thick oil.The HCl salt was prepared by dropwise addition of concentratedhydrochloric acid to a solution of the title compound in methanol,concentrated and recrystallized from methanol-acetone, mp 159° C. to161° C. IR(KBr): 3420, 1650cm⁻¹. MS: 421 (M⁺). ¹ H NMR (CD₃ OD): δ8.89(s, 1H), 8.72 (d, J=6.6 Hz, 1H), 8.15 (d, J=8.9 Hz, 2H), 7.89 (d, J=7.3Hz, 1H), 7.48 (t, J=6.9 Hz, 1H), 7.21 (d, J= 8.9 Hz, 2H), 4.29 (t, J=7Hz, 2H), 3.26 (m, 6H), 2.73 (s, 3H), 2.33 (m, 2H), 1.79-1.35 (m, 8H),1.02 (m, 6H).

Theor. C₂₆ H₃₅ N₃ O₂.3HCl.H₂ O: C, 56.88; H, 7.34; N, 7.65. Found: C,56.53; H, 7.00; N, 7.60.

EXAMPLE 92-(4-Dibutylaminopropoxybenzoyl)-5,7-dimethylimidazo[1,2-a]pyridine

The title compound was prepared in accordance with Example 8 by reacting4,6-dimethyl-2-aminopyridine (0.8 g, 6.6 mmol) withβ-bromo-α-keto-(4-chloropropoxy)propiophenone and then reacting theresulting product with dibutylamine to yield 1.3 g of the free base(100% yield) which was converted to the HCl salt, mp 106° C. to 108° C.IR(KBr): 3440, 1650 cm⁻¹. MS: 435 (M⁺). ¹ H NMR (CD₃ OD): δ8.68 (s, 1H),8.17 (d, J=8.9 Hz, 2H), 7.63 (s, 1H), 7.32 (s, 1H), 7.21 (d, J=8,9 Hz,2H), 4.30 (t, J=6.2 Hz, 2H), 3.25 (m, 6H), 2.87 (s, 3H), 2.62 (s, 3H)2.36 (m, 2H), 1.85-1.35 (m, 8H), 1.02 (m, 6H).

Theor. C₂₇ H₃₇ N₃ O₂.3HCl: C, 59.50; H, 7.40; N, 7.71. Found: C, 60.02;H, 7.76; N, 7.85.

p EXAMPLE 102-(4-Dibutylaminopropoxybenzoyl)-7-methylimidazol[1,2-a]pyridine

methylimidazo[1,2-a]pyridine

4-Methyl-2-aminopyridine (1.4 g, 12.5 mmol) was reacted withβ-bromo-α-keto-(4-chloropropoxy)propiophenone as described in Example 8.The resulting product was reacted with dibutylamine as described inExample 8 to produce 2.9 g (75% yield) of the free base of the titlecompound which was converted to the HCl salt, mp 210° C. to 212° C.IR(KBr): 3460, 2640, 1650 cm⁻¹. MS: 421 (M⁺). ¹ H NMR (CD₃ OD): δ8.89(s, 1H), 8.77 (d, J=7.5 Hz, 2H), 8.12 (d, J=8.9 Hz, 2H), 7.77 (s, 1H),7.48 (d, J=7.5 Hz, 2H), 7.20 (d, J=8.9 Hz, 2H), 4.30 (t, J=5.7 Hz, 2H),3.38-3.16 (m, 6H), 2.65 (s, 3H), 2.35 (m, 2H), 1.81-1.34 (m, 8H), 1.02(m, 6H).

Theor. C₂₆ H₃₅ N₃ O₂.3HCl: C, 58.81; H, 7.21; N, 7.91. Found: C, 58.79;H, 7.00; N, 7.79.

EXAMPLE 112-(4-Dibutylaminopropoxybenzoyl)-8-benzyloxyimidazo[1,2-a]pyridine

The title compound was prepared according to Example 8 by reacting3-benzyloxy-2-aminopyridine (2.2 g, 11 mmol) withβ-bromo-α-keto-(4-chloropropoxy)propiophenone and then reacting theresulting product with dibutylamine to produce 1.4 g (52% yield) of thefree base which was converted to the HCl salt, mp 171° C. to 174° C.1R(KBr): 3400, 2620, 1660 cm⁻¹. MS: 513 (M⁺). ¹ H NMR (CD₃ OD): δ8.87(s, 1H), 8.44 (d, J=7.0 Hz, 1H), 8.12 (d, J=7.0 Hz, 2H), 7.66-7.35 (m,7H), 7.20 (d, J=7 Hz, 2H), 5.51 (brs, 2H) 4.31 (t, J=5.0 Hz, 2H),3.41-3.14 (m, 6H), 2.32 (m, 2H), 1.65-1.34 (m, 8H), 1.02 (m, 6H).

Theor. C₃₂ H₃₉ N₃ O₃.2HCl.1/2H₂ O: C, 64.53; H, 7.11; N, 7.06. Found: C,64.13; H, 7.22; N, 7.00.

EXAMPLE 12

2-(4-Dibutylaminoproxybenzoyl)-6-bromoimidazo[1,2-a]pyridine

5-Bromo-2-aminopyridine (2.7 g, 15.7 mmol) was reacted withβ-bromo-α-keto-(4-chloropropoxy)-propiophenone as described in Example8. The resulting product was reacted with dibutylamine as described inExample 8 to produce 4.5 g (60% yield) of the free base of the titlecompound which was converted to the HCl salt, mp 214° C. to 216° C.IR(KBr): 3420, 2600, 2440, 1650 cm⁻¹. MS: 442 (M⁺). ¹ H NMR (CD₃ OD):δ9.20 (s, 1H), 8.86 (s, 1H), 8.21 (d, J=8.7 Hz, 2H), 8.07-7.80 (m, 2H),7.17 (d, J=8.7 Hz, 2H), 4.25 (m, 2H), 1.78-1.25 (m, 8H), 0.95 (m, 6H).

Theor. C₂₅ H₃₂ BrN₃ O₂.2HCl: C, 53.68; H, 6.13; N, 7.51. Found: C,53.28; H, 6.30; N, 7.52.

When in the above procedure, 2-aminopyridine or3-hydroxy-2-aminopyridine is used in place of 5-bromo-2-aminopyridine,2-(4-dibutylaminopropoxybenzoyl)imidazo[1,2-a]pyridin or2-(4-dibutylaminopropoxybenzoyl)-8-hydroxyimidazo(1,2-alpyridine isobtained.

When in any of the above procedures of Examples 8, 9, 10, 11 or 12,dimethylamine, diethylamine, dipropylamine, dipentylamine ordihexylamine is used in place of dibutylamine, the corresponding2-(4-dimethyl-, 2-(4-diethyl-, 2-(4-dipropyl-, 2-(4-dipentyl-, or2-(4-dihexylaminopropoxybenzoyl)-substituted imidazo[1,2-a]pyridinederivatives are obtained.

EXAMPLE 133-(4-Dibutylaminopropoxybenzoyl)-8-methylimidazo[1,2-a]pyridine

To a solution of 3-methyl-2-aminopyridine (5.0 g, 46 mmol) in toluene(60 ml) was added dimethylformamide dimethylacetal (7.9 g, 6.2 mmol)dropwise and stirred at reflux for 6 hours. The mixture was concentratedto give 3-methyl-2-dimethylaminoamidinopyridine as an oil (7.0 g, 94%yield). ¹ H NMR (CDCl₃): δ8.33 (s, 1H), 8.12-8.05 (m, 1H), 7.42-7.33 (m,1H) 6.79 (d,d, J=4.9 Hz, 1H), 3.08 (s, 6H), 2.30 (s, 3H).

A mixture of 3-methyl-2-dimethylaminoamidinopyridine (2.8 g, 17 mmol)and α-bromo-p-hydroxyacetophenone (3.6 g, 17 mmol) in ethanol (10 ml)was stirred at reflux for 2 hours. The mixture was cooled to roomtemperature and the resulting precipitate was collected by filtrationand washed with cold ethanol to give3-(4-hydroxybenzoyl)-8-methylimidazo[1,2-a]pyridine (2.6 g, 63% yield).¹ H NMR (DMSO): δ9.68 (d, J=8 Hz, 1H), 8.74 (s, 1H), 8.00-7.61 (m, 4H),7.21 (d, J=7.2 Hz, 2H), 2.74 (s, 3H).

A mixture of 3-(4-hydroxybenzoyl)-8-methylimidazo[1,2-a]-pyridine (2.3g, 9.6 mmol), dibutylaminopropyl chloride (6.8 g, 33 mmol) and potassiumhydroxide (1.3 g, 23 mmol) in methanol (60 ml) was stirred at reflux for96 hours. The mixture was concentrated and the resulting oil was flashchromatographed (silica gel, 2.5% methanol in diethyl ether) to give 1.3g (31% yield) of the free base of the title compound. The HCl salt wasprepared by dropwise addition of concentrated hydrochloric acid to asolution of the free base in methanol, concentrated and recrystallizedfrom acetone-ether to give the HCl salt of the title compound as anoff-white solid, mp 105° C. to 107° C. lR(KBr): 3440, 2640, 1645, 1605cm⁻¹. MS: 421 (M⁺). ¹ H NMR (CD₃ OD): δ9.66 (d, J=8 Hz, 1H), 8.74 (s,1H), 8.00-7.61 (m, 4H), 7.20 (d, J=7.2 Hz, 2H), 4.29 (t, J=5 Hz, 2H),3.41-3.15 (m, 6H), 2.75 (s, 3H), 2.31 (m, 2H), 1.80-1.42 (m, 8H), 1.02(m, 6H).

Theor. C₂₆ H₃₅ N₃ O₃.3HCl: C, 58.81; H, 7.21; N, 7.91. Found: C, 58.77;H, 7.17; N, 7.98. EXAMPLE 143-(4-Dibutylaminopropoxybenzoyl)-6-bromoimidazo[1,2-a]pyridine

The title compound was prepared according to Example 13 by utilizing5-bromo-2-aminopyridine (5.0 g, 28.9 mmol) in place of the3-methyl-2-aminopyridine to produce 1.1 g (8.8% yield) of the free basewhich was converted to the HCl salt, mp 162° C. to 165° C. IR(KBr):3430, 2650, 1650, 1610 cm⁻¹. MS: 442 (M-C₃ H₇ ⁺). ¹ H NMR (CD₃ OD):δ9.92 (m, 1H), 8.66 (s, 1H), 8.23 (d,d, J=9.5, 1.8 Hz, 1H), 8.06-7.95(m, 3H), 7.18 (d, J=8.9 Hz, 2H), 4.28 (t, J=5.5 Hz, 2H), 3.39-3.14 (m,6H), 2.32 (m, 2H), 1.80-1.34 (m, 8H), 1.02 (m, 6H).

For C₂₅ H₃₂ BrN₃ O₂.3HCl.2H₂ O Theor.: C, 47.52; H, 6.22; N, 6.65; Cl,17.85 Found: C. 47.60; H, 5.68; N, 6.66; Cl, 17.94.

When in the above procedure, 2-aminopyridine, 4-methyl-2-aminopyridine,3-benzyloxy-2-aminopyridine, 4,6-dimethyl-2-aminopyridine, or3-hydroxy-2-aminopyridine is used in the starting material, thecorresponding 3-(4-dibutylaminopropoxybenzoyl)imidazo[1,2-a]pyridine,3-(4-dibutylaminopropoxybenzoyl)-7-methylimidazo [1,2-a]pyridine,3-(4-dibutylaminopropoxybenzoyl)-8-benzyloxyimidazo [1,2-a]pyridine,3-(4-dibutylaminopropoxybenzoyl)-5,7-dimethylimidazo[1,2-a]pyridine, or3-(4-dibutylaminopropoxybenzoyl)-8-hydroxyimidazo[1,2-a]pyridine isobtained.

When in any of the above procedures of Examples 13 and 14,dibutylaminoethyl chloride, dimethylaminopentyl chloride,diethaminobutyl chloride or dipentylaminopropyl chloride is employed asthe alkylating agent, the corresponding 3-(4-dibutylaminoethyoxy-,3-(4-dimethylaminopentoxy-, 3-(4-diethylaminobutoxy-, or3-(4-dipentylaminopropoxy- benzoyl)-substituted imidazo[1,2-a]pyridinesare obtained.

EXAMPLES 15 Local Anesthetic Activity

The local anesthetic activity of the above compounds was determined asfollows.

The test compounds were dissolved or suspended in a 0.5% aqueousmethylcellulose solution containing 0.4% (v/v) of Tween 80, thepolyoxyethylene derivative of a sorbitan ester. Doses of up to 100 mg/kgwere administered orally by gavage tube to groups of three male albinoovernight-fasted mice (18 to 24 g) which were observed intermittentlyfor one hour. The mice were gently restrained and 0.05 ml of a 1% (w/v)solution or suspension of the test compound was injected into thequadriceps femoris muscle of one hind leg. Five minutes later, the miceare individually placed on a wire mesh screen. The wire mesh screen wasthen inverted. Compounds that posses local anesthetic activity impairedthe ability of the mice to grasp the inverted screen with the injectedleg. The response to the test compounds was compared to a similarlytreated vehicle control group of mice.

                  TABLE 1                                                         ______________________________________                                        Local Anesthetic Effects of Representative                                    2- or 3- Aryl substituted imidazo[1,2-a]-                                     pyridines in Overnight-fasted Mice                                            Compound   Concentration (in %) of Compound                                   (Example)  Causing Local Anesthetic Activity                                  ______________________________________                                        1          0.1                                                                2          0.001                                                              3          1.0                                                                4          0.1                                                                5          1.0                                                                6          0.1                                                                7          0.1                                                                8          1.0                                                                9          1.0                                                                10         1.0                                                                11         0.1                                                                12         1.0                                                                13         0.1                                                                14         0.1                                                                ______________________________________                                    

What is claimed:
 1. A compound of the formula ##STR7## where X is hydrogen, one or more of halogen, hydroxy, alkoxy having 1-3 carbon atoms, benzyloxy, or C₁ -C₆ alkyl,R is H or Ar: R₁ is H, CH₃ or Ar: Ar is ##STR8## R₂ is C₁ -C₆ alkyl; n is 0 or 1 when R is Ar or 1 when R₁ is Ar; andm is 2-6, with the provision that both R and R₁ are not Ar at the same time and that at least one of R and R₁ is Ar.
 2. A compound of claim 1 wherein X is hydrogen, bromo, hydroxy, benzyloxy, methyl or dimethyl, R₂ is butyl and m is
 3. 3. A compound of claim 1 selected from the group consisting of 2-(4-dibutylaminopropoxyphenyl)imidazo[1,2-a]pyridine; 2-(4-dibutylaminopropoxyphenyl)-8-methylimidazo [1,2-a]pyridine; 2-(4-dibutylaminopropoxyphenyl)-6-bromoimidazo [1,2-a]-pyridine; 2-(4-dibutylaminopropoxyphenyl)-7-methylimidazo-[1,2-a]pyridine; 2-(4-dibutylaminopropoxyphenyl)-3,8-dimethyl imidazo [1, 2-a]pyridine; 2-(4-dibutylaminopropoxyphenyl)-8-hydroxyimidazo[1,2-a]pyridine; and 2-(4-dibutylaminopropoxyphenyl)-8-benzoyloxyimidazo[1,2-a]pyridine.
 4. A compound of claim 1 selected from the group consisting of 2-(4-dibutylaminopropoxybenzoyl)-8-methylimidazo[1,2-a]-pyridine; 2-(4-dibutylaminopropoxybenzoyl)-5,7-dimethylimidazo[1,2-a]pyridine; 2-(4-dibutylaminopropoxybenzoyl)-7-methylimidazo[1,2-a]pyridine; 2-(4-dibutylaminopropoxybenzoyl)-8-benzyloxyimidazo[1,2-a]pyridine; and 2-(4-dibutylaminopropoxybenzoyl)-6-bromoimidazo[1,2-a]pyridine.
 5. A compound of claim 1 selected from the group consisting of 3-(4-dibutylaminopropoxybenzoyl)-8-methylimidazo[1,2-a]-pyridine and 3-(4-dibutylaminopropoxybenzoyl)-6-bromoimidazo[1,2-a]pyridine. 